期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 123, 期 1, 页码 179-188出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI64617
关键词
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资金
- National Institutes of Health [HL106019, HL075662, HL054591]
- Swedish Research Council
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL087123, R01HL107497, R00HL097021, R01HL106019, R01HL075662, P01HL054591] Funding Source: NIH RePORTER
TLR activation on CD11c(+) DCs triggers DC maturation, which is critical for T cell activation. Given the expansion of CD11c(+) DCs during the progression of atherosclerosis and the key role of T cell activation in atherogenesis, we sought to understand the role of TLR signaling in CD11c(+) DCs in atherosclerosis. To this end, we used a mouse model in which a key TLR adaptor involved in DC maturation, MYD88, is deleted in CD11c(+) DCs. We transplanted bone marrow containing Myd88-deficient CD11c(+) DCs into Western diet-fed LDL receptor knockout mice and found that the transplanted mice had decreased activation of effector T cells in the periphery as well as decreased infiltration of both effector T cells and Tregs in atherosclerotic lesions. Surprisingly, the net effect was an increase in atherosclerotic lesion size due to an increase in the content of myeloid-derived inflammatory cells. The mechanism involves increased lesional monocyte recruitment associated with loss of Treg-mediated suppression of MCP-1. Thus, the dominant effect of MYD88 signaling in CD11c(+) DCs in the setting of atherosclerosis is to promote the development of atheroprotective Tregs. In the absence of MYD88 signaling in CD11c(+) DCs, the loss of this protective Treg response trumps the loss of proatherogenic T effector cell activation.
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